Several quaternary ammonium salts are known in the literature and useful in different technical fields. Their preparation usually includes the alkylation of tertiary amines as final step but most of these preparation methods require long reaction times.
For example, U.S. Pat. No. 2,956,062 describes batch synthetic methods for the alkylation of cyclic tertiary amines (N-substituted 3-pyrrolidinols) by reaction with an excess of an alkylating agent in a suitable solvent such as ether or ethyl acetate. The reaction requires several hours and even days to be completed.
U.S. Pat. No. 3,813,441 describes a continuous process for the production of quaternary aliphatic ammonium chlorides from aliphatic amines having a long chain by reaction with methyl chloride and an aqueous solution of an alkali hydroxide in a low-boiling solvent under pressure. The reaction by-product sodium chloride has to be removed continuously by filtration.
EP 0 288 857 describes a solvent-free process for the quaternization of tertiary amines with alkyl halides in a molar ratio ranging from 1:3 to 1:8 at elevated pressures (up to 27.5 bar).
U.S. Pat. No. 5,041,664 describes a continuous process for the quaternization of long chain tertiary amines with alkyl chlorides, heterogeneously catalyzed by a metal oxide.
U.S. Pat. No. 5,491,240 describes the preparation of quaternary ammonium compounds useful as fabric softeners and/or conditioning agents for the skin or hair. The preparation includes the quaternization of tertiary amines wherein the alkylating agent is added stage wise. The reaction time is about 10 hours.
EP 0 869 114 describes a batch process for the quaternization of ester-amines which requires reaction times of at least 24 hours. The resultant quaternary compounds are useful for softening applications.
WO 2011/091197 describes the preparation of quaternized N,N-dialkylaminoethyl(meth)acrylates useful as intermediates for cationic flocculant polymers. The preparation includes a two-phase process for the quaternization of N,N-dialkylaminoethyl(meth)acrylates wherein the phase containing the product is continuously removed from the tank reactor.
Some cyclic quaternary ammonium salts such as, for example, tiotropium bromide (chemical name: 1α,2β,4β,7β)-7-[(hydroxy-di-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane bromide) of formula
marketed under the trademark Spiriva®,    glycopyrronium bromide (chemical name: 3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium bromide) of formula
marketed under the trademark Robinul®, and ipratropium bromide (chemical name: [8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3.2.1]oct-3-yl]-3-hydroxy-2-phenyl-propanoate) of formula
marketed under the trademark Atrovent®, are known anticholinergic drugs with different applications, mainly for the treatment of chronic obstructive pulmonary disease (COPD).
Their preparation usually includes the alkylation of the corresponding cyclic tertiary amines as a final step but most of these preparation methods require long reaction times and further purification to achieve a suitable pharmaceutical grade.
For example, U.S. Pat. No. 5,610,163 describes the preparation of tiotropium bromide and its analogs by reaction of the corresponding cyclic tertiary amines dissolved in methylene chloride/acetonitrile with a solution of methyl bromide in acetonitrile at room temperature for 24 hours.
There is still the need of an efficient improved process, particularly of an efficient continuous process for the preparation of cyclic quaternary ammonium compounds. We have now found a method for the continuous alkylation of cyclic tertiary amines, particularly useful for the production of cyclic quaternary ammonium compounds with high purity as required for pharmaceutical use, which is more efficient than the known quaternization processes.